Prevalence of persistent asymptomatic proteinuria in HIV-infected outpatients and lack of correlation with viral load.

AIM: Human immunodeficiency virus-associated nephropathy (HIVAN) is projected to be a leading cause of end-stage renal disease (ESRD) in young African American men in the new millennium. Little is known about the early natural history of the disease, including the prevalence of asymptomatic nephropathy. The primary aim of this study was to define the prevalence of persistent asymptomatic proteinuria in a contemporary, ambulatory human immunodeficiency virus- (HIV) infected population. The secondary aim was to correlate the presence of persistent proteinuria with measures of HIV disease. METHODS: Using a readily available screening tool, the urine dipstick, we determined the prevalence of persistent asymptomatic proteinuria in the outpatient VA Connecticut (VA CT) Healthcare System West Haven HIV Clinic population. We compared the presence of persistent proteinuria with measures of HIV viral disease. RESULTS: The prevalence of persistent asymptomatic proteinuria was 14% (7 of 49 patients). The presence of persistent proteinuria was not correlated with viral load. CONCLUSIONS: A significant prevalence of occult renal disease exists in the asymptomatic HIV-seropositive outpatient population and is not correlated with viral load.

Self detoxication by amphetamine dependent patients: a pilot study.

Fifty current or past amphetamine dependent clients attending a Community Drug and Alcohol Team service took part in structured interviews about their previous attempts to stop using amphetamine. Thirty three had made a total of 47 attempts at self detoxication; 15 had undergone enforced withdrawal and ten had previously sought medical treatment. A total of 86% of subjects described significant withdrawal symptoms on stopping use of amphetamines. Increased use of other drugs was commonly reported as a means of coping with withdrawal, psycho-social techniques being used less systematically. The implications for the provision of attractive, effective treatments are discussed.

Doctor-patient communication: a study of junior house officers.

This study evaluates junior house officers' perceptions of their communication skills with cancer patients; the usefulness of their undergraduate communication skills training; and their sources of emotional support. All 42 junior house officers employed at Guy's and Lewisham Hospitals in August 1994 were interviewed using a study-specific, semi-structured interview. Sixty-seven per cent of junior house officers felt they had adequate communication skills in relation to medical issues, but only 36% felt they had adequate skills in relation to psychological issues. Thirty-one per cent of doctors reported that they never, or nearly never, enquired about the emotional adjustment of dying patients. Lack of time was the most commonly reported reason for avoiding asking about psychological problems (62% of junior house officers), followed by wishing to avoid awkward questions (51%) and inadequacy of skills to deal with such issues (44%). Ninety-eight per cent of junior house officers had attended the 1-week undergraduate communication skills course at Guy's and St Thomas's Hospital Medical School (UMDS). Sixty-seven per cent of those who had attended found the course helpful and 62% felt they would benefit from further training as junior house officers. Seventy-four per cent felt they could discuss their work-related concerns with colleagues and 95% felt they could talk to friends. In contrast only about 9% felt they could, if needed, talk to a counsellor. Although the majority of the junior house officers reported benefit from their communication skills training, the course does not appear to be meeting all their communication training needs. Junior house officers require further training opportunities at the undergraduate and postgraduate levels. Traditional counselling services for junior house officers may not be meeting their support needs.

The Myxococcus xanthus asgA gene encodes a novel signal transduction protein required for multicellular development.

The Myxococcus xanthus asgA gene is one of three known genes necessary for the production of extracellular A-signal, a cell density signal required early in fruiting body development. We determined the DNA sequence of asgA. The deduced 385-amino-acid sequence of AsgA was found to contain two domains: one homologous to the receiver domain of response regulators and the other homologous to the transmitter domain of histidine protein kinases. A kanamycin resistance (Kmr) gene was inserted at various positions within or near the asgA gene to determine the null phenotype. Those strains with the Kmr gene inserted upstream or downstream of asgA are able to form fruiting bodies, while strains containing the Kmr gene inserted within asgA fail to develop. The nature and location of the asgA476 mutation were determined. This mutation causes a leucine-to-proline substitution within a conserved stretch of hydrophobic residues in the N-terminal receiver domain. Cells containing the insertion within asgA and cells containing the asgA476 substitution have similar phenotypes with respect to development, colony color, and expression of an asg-dependent gene. An analysis of expression of a translational asgA-lacZ fusion confirms that asgA is expressed during growth and early development. Finally, we propose that AsgA functions within a signal transduction pathway that is required to sense starvation and to respond with the production of extracellular A-signal.

The use of granulocyte colony-stimulating factor to deliver four cycles of ifosfamide and epirubicin every 14 days in women with advanced or metastatic breast cancer.

Twenty patients with locally advanced or metastatic breast cancer were treated with four cycles of ifosfamide/mesna 5 g m-2 and epirubicin 60 mg m-2 every 14 days with granulocyte colony-stimulating factor (G-CSF, Filgrastim). Complete remission occurred in six out of the 20 patients (30%, 95% confidence interval 12-54%) and there were 12 partial responders (60%, 95% confidence interval 37-81%), thus giving an overall response rate of 90% (95% confidence interval 63-97%). Two patients had progressive disease. The median duration of response for those patients with metastatic disease was 7.3 (1.3-20.1+) months. The median survival time for these patients was 15 (5.3-27.9+) months. Of the four patients treated with locally advanced disease three achieved a complete clinical response and one a partial response. Three out of four of these patients subsequently underwent a mastectomy, and in one of these no viable tumour was seen. Our conclusion is that this regimen is excellent palliation for metastatic disease and possibly useful neoadjuvant treatment.

Evidence that asgB encodes a DNA-binding protein essential for growth and development of Myxococcus xanthus.

The asg mutants of Myxococcus xanthus are defective in production of extracellular A-signal, which serves as a cell density signal for fruiting-body development. The DNA sequence of asgB, one of the three asg genes, was determined. The deduced amino acid sequence of AsgB contains a DNA-binding helix-turn-helix motif near the C terminus. This putative helix-turn-helix is highly similar to the helix-turn-helix in region 4.2 of major sigma factors, which is the region that recognizes and interacts with -35 sequences of promoters. We propose that AsgB is a transcription factor that binds to DNA sequences similar to the -35 hexamer, TTGACA. Analyses of asgB RNA levels and expression of an asgB-lacZ translational fusion indicate that expression of asgB remains fairly constant during the transition from growth into early development. The mutation within the asgB480 allele was identified as an A-to-G transition that results in a threonine-to-alanine substitution in the predicted protein product. Attempts to replace the wild-type copy of asgB with a null allele failed, indicating that asgB may be essential for growth.

Results of chemotherapy using ifosfamide with doxorubicin in advanced breast cancer.

Ifosfamide has single agent activity in advanced breast cancer and may potentiate the activity of doxorubicin. The combination of ifosfamide 5 g/m2 and doxorubicin 40 mg/m2 every 3 weeks for 4 cycles was used to treat 77 patients with advanced breast cancer. Fifty three patients had not received prior chemotherapy. All patients had one or more poor prognostic features, including tumor expression of epidermal growth factor receptor in 11/12 tested. The overall response rate was 74% (95% confidence intervals 62%-83%). The median survival was 9.4 months. The principal toxicities were febrile neutropenia and ifosfamide encephalopathy each in 6% of patients. A high percentage of the projected dose intensity was administered. This is a highly active combination with acceptable toxicity in advanced breast cancer, although the long term survival remains poor. Further exploration of ifosfamide in combination chemotherapy for advanced breast cancer is warranted.

High-dose (480 mg/day) tamoxifen with etoposide: a study of a potential multi-drug resistance modulator.

Tamoxifen and its principle metabolite N-desmethyltamoxifen can modulate multi-drug resistance in vitro. Tamoxifen 480 mg/day was given for 6 days with oral etoposide on days 4-6 to 17 patients with advanced solid tumours. Venous thrombosis (2 patients), reversible neurological toxicity (1 patient), and WHO grade III nausea/vomiting (3 patients) related to tamoxifen were observed but overall toxicity was manageable. One partial response occurred in 15 assessable patients. Mean plasma concentrations of tamoxifen and N-desmethyltamoxifen increased to 4.3 mumol/l and 2.7 mumol/l, respectively, by day 6. Plasma concentrations corresponding to active in vitro levels were attained by most patients.

Oral verapamil with chemotherapy for advanced non-small cell lung cancer: a randomised study.

To determine if the chemotherapy resistance of non-small cell lung cancer could be modified by oral verapamil, 72 patients were entered into a randomised trial of verapamil plus chemotherapy vs the same chemotherapy alone. Verapamil 480 mg day-1 was given for 3 days starting 24 h prior to chemotherapy which consisted of bolus vindesine 7 mg followed by ifosfamide/mesna 5 g m-2 over 24 h, followed by mesna alone for a further 8 h. Cycles were repeated every 3 weeks for up to six courses. Sixty-six patients were eligible for tumour response analysis and responses occurred in 41% of those randomised to chemotherapy plus verapamil and in 18% of those randomised to chemotherapy alone (P = 0.057). Median survival from start of treatment was significantly better in the verapamil arm (P = 0.02). Toxicity of the combination of chemotherapy plus verapamil was principally neurological and was manageable. Thus the addition of oral verapamil to vindesine/ifosfamide chemotherapy is feasible and in this study was associated with improved outcome. Further confirmation of these observations is required in non-small cell lung cancer, a tumour characterised by resistance to conventional chemotherapy.

Long-term oral etoposide in metastatic breast cancer: clinical and pharmacokinetic results.

To evaluate the activity of long-term, single-agent oral etoposide against advanced breast cancer, this study employed etoposide 50 mg/day and 100 mg/day (given over 14 days) in previously treated and chemotherapy-naive patients with histologically confirmed, recurrent or metastatic breast cancer. Of 38 patients, 24 had had chemotherapy, 34 had prior radiotherapy, and 31 had received hormone therapy. Etoposide courses in both treatment groups were repeated every 4 weeks for at least two courses; delays were instituted when patients' total leukocyte nadir fell to or below 3.0 x 10(9)/l. Dose reductions were made in the 100-mg group (to 50 mg/day) if World Health Organization leukopenia grade 3 or higher was present. Plasma pharmacokinetic profiles were measured in selected patients to assess inter- and intrapatient variability in etoposide's oral bioavailability. No complete responses were achieved among the 36 patients evaluable for response, but eight patients had a partial response. Responses were more frequent at the 100-mg dose and in previously untreated patients (seven of eight partial responders had not had previous chemotherapy). Median duration of response was 16 weeks (range, 7 to 46). Myelosuppression (variable and unpredictable) and alopecia (universal) were the notable toxicities. Pharmacokinetic analyses of oral bioavailability revealed significant interpatient variability, but much less intrapatient variability when successive etoposide courses in individual patients were evaluated. Despite the relatively small number of patients in this study, the responses achieved by previously untreated patients suggest etoposide's value against breast cancer. Further trials should use pharmacokinetic studies to assess bioavailability as well as to help define 'target' etoposide doses, based on plasma etoposide levels, during treatment.

Parallel changes in the blood levels of abnormally-fucosylated haptoglobin and alpha 1,3 fucosyltransferase in relationship to tumour burden: more evidence for a disturbance of fucose metabolism in cancer.

Levels of an abnormally-fucosylated form of the serum glycoprotein, haptoglobin (FHp) and an enzyme, alpha 1,3 fucosyltransferase (FT) have been measured in blood specimens from women with carcinoma of the ovary or breast who are undergoing chemotherapy. The levels of FHp and FT increased if the women had progressive disease and decreased if they showed complete response to therapy. The statistical correlation between the blood concentrations of these two substances is very strong (P less than 0.0001, chi 2 test). These results and recent studies of fucosyltransferases and cell adhesion molecules from other laboratories, suggest that there are important changes in fucose metabolism in cancer which are worthy of further investigation.

A phase II trial of goserelin (Zoladex) in relapsed epithelial ovarian cancer.

Thirty patients with advanced epithelial ovarian cancer were treated with the luteinising hormone releasing agonist, goserelin. There were two partial responses lasting 40 and 105 weeks respectively. In addition five patients had disease stabilisation lasting 25, 35, 40, 66 and 70 weeks respectively and 23 patients had progressive disease. No significant or unexpected toxicities occurred. This minimally toxic therapy halted disease progression for 6 months or more in 23% of patients, the majority of whom were heavily pretreated. There were five early deaths due to disease progression. The use of goserelin in patients with epithelial ovarian cancers resistant to or relapsing soon after first line platinum based chemotherapy needs to be further evaluated.

Prediction of claudication pain from clinical measurements obtained at rest.

The ability to predict claudication pain during single-stage (S) and progressive (P) treadmill protocols from clinical measurements obtained at rest was examined. Peripheral hemodynamic measurements from the more severely diseased lower limb and medical history data were obtained from 56 claudicant patients during supine rest immediately preceding S (1.5 mph and 7.5% grade) and P (2 mph, 0% grade with 2% increase every 2 min) treadmill protocols. Distance walked to onset of claudication pain (CPD) and to maximal pain (MPD) during both protocols were recorded. The claudication distances during the S protocol were not correlated with either the peripheral hemodynamic or medical history variables. In contrast, CPD and MPD during the P protocol were predicted (P less than 0.05) by ankle/brachial systolic blood pressure index (ABI) (quadratic relationship), laterality of claudication pain (1 = unilateral, 2 = bilateral), and gender (1 = female, 2 = male) from the following regression equations: CDP (m) = 159.9 - (321.8 x ABI) + (445.6 x ABI2) - (93.5 x laterality) + (99.0 x gender), R = 0.74, R2 = 0.55, adjusted R2 = 0.53, SEE = 110.5, P less than 0.0001; and MPD (m) = 83.1 + (195.0 x ABI) + (174.0 x ABI2) - (76.4 x laterality) + (114.2 x gender), R = 0.76, R2 = 0.58, adjusted R2 = 0.55, SEE = 138.3, P less than 0.0001. It is concluded that the regression equations for the prediction of CPD and MPD may be used to quickly estimate the functional severity of peripheral vascular occlusive disease in clinical settings where treadmill testing is not feasible or is impractical.

Response to mitoxantrone in advanced breast cancer: correlation with expression of c-erbB-2 protein and glutathione S-transferases.

Sixty-eight patients with advanced breast cancer were treated with mitoxantrone and clinical responses assessed. Expression of c-erbB-2 protein and cytosolic glutathione S-transferase (GST) isoenzymes pi, alpha and mu by the primary tumours of these patients was determined immunohistochemically, and correlated with treatment response. Tumours overexpressing c-erbB-2 (n = 16, 23%) showed a lower response rate (50% vs 58%) and shorter duration of response to treatment, compared with c-erbB-2 negative tumours. These associations were not statistically significant but survival following start of treatment was significantly shorter in the c-erbB-2 positive group. For each GST isoenzyme, the response rate and duration of response of the group showing enzyme expression did not differ significantly from those with negatively staining tumours. These data do not support a role for expression of GSTs alone in resistance to mitoxantrone monotherapy in advanced breast cancer. The poorer post treatment survival of patients with c-erbB-2 positive tumours suggests they could be selected for more intensive treatment regimens.

Intermittent high-dose tamoxifen as a potential modifier of multidrug resistance.

In vitro tamoxifen reverses multidrug resistance (MDR). To evaluate the clinical potential of using tamoxifen in this way, intermittent high-dose tamoxifen was combined with oral etoposide in 86 patients. At 320 mg/day tamoxifen for 6 days, mean plasma levels of tamoxifen in 11 patients increased from 453 ng/ml (range 269-664) on day 2 to 984 ng/ml (578-1336) on day 6. Of 31 patients who had plasma tamoxifen measured during the time of etoposide administration (days 4-6), 13(43%) were over 1111 ng/ml (3 mumol/l), an active in vitro level. Potentially active levels of the principal metabolite, N-desmethyl tamoxifen, were also obtained but accumulation was slower. Emesis and thromboembolism were toxicities. Tamoxifen is a modifier of MDR, a role that warrants further clinical studies.